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Psychosomatics 47:399-407, September-October
doi: 10.1176/appi.psy.47.5.399
© 2006 Academy of Psychosomatic Medicine
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Epidemiology of Depression and Antidepressant Therapy After Acute Respiratory Failure

Craig Weinert, M.D., M.P.H., and William Meller, M.D.

Received June 21, 2005; revised October 10, 2005; accepted October 19, 2005. From the Depts. of Medicine and Psychiatry and Clinical Outcomes Research Center, Univ. of Minnesota Medical School, Minneapolis, MN. Address correspondence and reprint requests to Dr. Weinert, MMC 276, 420 Delaware St, SE Minneapolis, MN 55455. e-mail: weine006{at}umn.edu


  ABSTRACT

 
TOP
 ABSTRACT
INTRODUCTION
 METHOD
 RESULTS
 DISCUSSION
 REFERENCES
 
The authors enrolled 277 subjects with acute respiratory failure to describe the epidemiology of depressive disorders and antidepressant use during and after intensive care. By SCID criteria, the prevalence of major depressive episode at 2 months was 16%, and 16% had depressive disorder not otherwise specified. Mood disorder incidence was 25% or 28%, depending on methodology. Pre-ICU physical functioning and depression were associated with 2- and 6-month depression severity. At 2 months, the prevalence of antidepressant medication use was 49%, and the incidence was 28%. Depression and antidepressant pharmacotherapy are frequent during recovery from acute respiratory failure.


  INTRODUCTION

 
TOP
 ABSTRACT
 INTRODUCTION
METHOD
 RESULTS
 DISCUSSION
 REFERENCES
 
Every year, more than 1 million patients in the United States are admitted to an intensive care unit (ICU) because of acute respiratory failure.1 Acute respiratory failure is a serious medical condition with a 20%–30% 1-month case-fatality rate,2 and survivors often require prolonged and costly rehabilitation.3 Previous work has demonstrated the negative impact that depression (including non-severe depression) has on functional status, healthcare costs, and mortality4 in patients with chronic medical illnesses. In patients recovering from prolonged respiratory failure, previous studies have used different diagnostic and severity instruments and evaluated patients at different times after their illness (months to years), but depression of moderate-or-greater severity affects 12%–43% of ICU survivors.5–10

Our objective was to describe short- and medium-term psychiatric outcomes in patients requiring acute mechanical ventilation and to define predictors of post-ICU depression and antidepressant medication use. We also characterized, in a sample of seriously ill patients, the accuracy of a depression severity instrument compared to a gold-standard diagnostic interview.


  METHOD

 
TOP
 ABSTRACT
 INTRODUCTION
 METHOD
RESULTS
 DISCUSSION
 REFERENCES
 
Study Design and Eligibility Criteria
We conducted a prospective cohort study in the medical and surgical ICUs at the primary teaching hospital of the University of Minnesota Medical School. Subjects were age 18 years or older who required acute mechanical ventilation via an endotracheal tube for more than 36 hours. The major exclusion criteria were coma (without medications that depress consciousness) for >24 hours, mental retardation or chronic cognitive dysfunction of sufficient severity to preclude a standardized interview; craniotomy; or plans to initiate withdrawal of life-support (patients with Do-Not-Resuscitate orders or living wills were not excluded). The observational study design, including the use of proxies for initial enrollment and the re-consenting of subjects to ensure that they wished to continue in the study, was approved by the Institutional Review Board at the University of Minnesota.

Baseline Data Collection
Because of subjects’ initial severity of illness, proxies were approached for study enrollment in 98% of the cases. After complete description of the study to the proxies, we obtained written informed consent. Proxies were interviewed about the subject’s best functional status in the month before the ICU admission and prescription or use of psychiatric medications (especially antidepressant medications) before ICU admission. We reviewed medical records for documentation of psychiatric medication use. Low-dose amitriptyline (≤50 mg), doxepine, or trazadone for sleep or neuropathy and bupropion prescribed for smoking cessation were not considered antidepressant medications in this study.

Follow-up Methods
If the subject was residing within 150 miles, we scheduled an in-person interview after 2 months. If the interview was completed, subjects were paid $50. More than 90% of the interviews were conducted in the home or facility where the subject was currently residing. Subjects >150 miles away had telephone interviews that included all of the items in the in-person interview except the Structured Clinical Interview for DSM-IV Axis I, Non-Patient Version, 2.011 (SCID). All 6-month interviews were by telephone.

Subjects completed an Activities of Daily Living (ADL) assessment; SCID Mood and Alcohol and other substance-use modules; the Center for Epidemiologic Studies–Depression scale (CES–D), which measures subjects’ self-reported positive and negative mood symptom frequency during the previous week,12 and the Medical Outcomes Study 36-item quality-of-life and functional-status instrument (4-week recall; Version 1).13 To minimize mode-effect bias,14 while anticipating that some subjects would have impaired communication function, except for the SCID interview, all items and possible responses were read aloud while subjects viewed a large-print card with the response choices.

All 2-month interviews were conducted by a single interviewer (CW), who had completed 14 hours of SCID training. Major depressive episodes (MDE) were categorized into Major Depressive Disorder, Bipolar, and Others, as defined by the SCID algorithm. Subjects meeting the A1 (depressed mood most of the day, nearly every day), as indicated by subjective report (e.g., feels sad or empty) or observation by others (e.g., appears tearful) or A2 criteria (markedly diminished interest or pleasure in all, or almost all, activities during the day, nearly every day), as indicated either by subjective account or observation by others, but without full criteria for MDE were defined in this study as Depressive Disorder, Not Otherwise Specified or Mood Disorder due to a general-medical condition (GMC), with depressive features. Dysthymic diagnoses were not recorded. To estimate depression incidence, we used two methods to exclude baseline cases of depression:

Method 1: We eliminated patients for which proxies had answered affirmatively during the enrollment interview that the subject had been "in the last month, significantly depressed or down, most of the day, nearly every day for more than 2 weeks" (SCID A1 criterion).

Method 2: We eliminated patients who were taking, or had been prescribed, antidepressant medications in the previous 6 months. Antidepressant use was considered present if the proxy said the subject had been taking an antidepressant or an antidepressant was listed in any reviewed medical record during the previous 6 months.

Statistical Analysis
All tests were two-sided. Area under the receiver operating characteristics (ROC) curve (AUC) statistics estimated the discrimination of the CES–D instrument, as compared with SCID diagnoses. Least-squares regression was used to estimate baseline predictors of 2-month CES–D depression severity. Repeated-measures regression, with subject as the random factor, defined predictors of depression severity over time. We used Kaplan-Meier plots and Cox regression to estimate subjects’ probability of receiving an antidepressant prescription over time and log-rank statistics to compare differences between groups.


  RESULTS

 
TOP
 ABSTRACT
 INTRODUCTION
 METHOD
 RESULTS
DISCUSSION
 REFERENCES
 
Subject Recruitment and Baseline Characteristics
Nearly 1,000 intubated patients were screened over 20 months, and 277 subjects were enrolled (Figure 1); 96% of subjects were enrolled by a spouse, partner, or first-degree relative; 89% of living subjects were interviewed at 2 months; 87% of the interviews were in-person, and 94% of the in-person interviewees completed a SCID interview.


Figure 1
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FIGURE 1.  Flow of Subjects Through Study


Table 1 shows that subjects’ median best physical functioning (PF) in the month before ICU admission was substantially impaired and comparable to patients with severe emphysema who have a mean physical functioning score of 22.15 More than one-quarter were defined as depressed at baseline by proxies, and one-third had taken an antidepressant at some time during the 6 months before study enrollment.


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TABLE 1. Baseline Characteristics of Subjects Enrolled and Completing 2-Month Follow-Up



Subjects required mechanical ventilation for a median of 6 days, hospitalization for 22 days, and had a 2-month case-fatality rate of 32%. The main indication for mechanical ventilation was postoperative respiratory failure (35%); other illnesses included cardiac conditions (13%), pneumonia or acute lung injury (21%), and sepsis (10%). None were caused by intentional drug overdose. In all, 48% of survivors were discharged from the hospital to home, 39% to a rehabilitation facility, and 8% to a skilled nursing facility. After 2 months, 31% of survivors had not yet returned home. The actual interval between intubation and the 2-month follow-up was 71 days (standard deviation [SD]: 12; N=164).

Mood Disorders at 2-Month Follow-Up
Forty-four subjects (33%) who completed an in-person interview met at least SCID Criteria A1 or A2. Twenty-two (16%) met full criteria for MDE. Thirteen episodes were due to MDE, single episode; three were MDE, recurrent; five were mood disorder due to a general-medical condition with major depressive episode-like features; and one was bipolar disorder. Twenty-two subjects (16%) were classified as depressive disorder, not otherwise specified (DD NOS; N=21) or mood disorder due to a general-medical condition, with depressive features (N=1). Other, non-mood SCID diagnoses included current delirium (5%) and current substance abuse or dependence (2%). No depressed subject required psychiatric hospitalization during the study interval.

To estimate the incidence of depressive disorders, 104 SCID interviews were conducted on subjects without baseline depression as defined by a negative response to the A1 criteria by the proxy. Thirteen developed an MDE, and 16 developed DD NOS, for a combined incidence of 28%. Using a second method to exclude cases of pre-ICU depression, 87 SCID interviews were conducted on subjects without baseline depression, defined by the absence of pre-ICU antidepressants. Ten had a major depressive episode (MDE), and 12 had depressive disorder, not otherwise specified (DD NOS), for a combined incidence of 25%.

Patients with incident (defined by the proxy method) depression (MDE + DD NOS) during the 2-month interval had significantly lower 2-month physical functioning scores (13.6 [SD: 18.2] versus 43.0 [SD: 30.0]; t[87]=4.8; p<0.001) than patients with no active psychiatric diagnosis. Depressed patients were 2.5 times more likely to be residing in a healthcare facility at 2 months than were those without depression (63% versus 25%; {chi}2[1]=11.2; p=0.001).

Comparison of the CES–D and SCID
Figure 2 shows significant differences in the distribution of CES–D values for groups defined by three SCID categories, Major Depressive Episode (MDE), Depressive Disorder Not Otherwise Specified (DD NOS), and No Mood Diagnosis (Kruskal-Wallis test, df=2, p<0.001). The area under the ROC curve (AUC) for MDE was 0.94 (95% confidence interval [CI]: 0.89–0.99), which is very good discrimination. The AUC for MDE or DD NOS was slightly less, at 0.91 (95% CI: 0.86–0.97). Table 2 shows test characteristics for the CES–D at threshold cut-points of ≥1612 and ≥2116 against diagnoses of MDE (N=22) or MDE or DD NOS (N=44). The sensitivity decreased and the specificity increased as the threshold was raised from 16 to 21. Using the combined SCID depression categories, the positive predictive value of the CES–D score remained high (0.82 and 0.83) whether a cut-off value of 16 or 21 was used. In all, 27% of all subjects (including telephone interviews) had scores ≥16. Analyzing only subjects without pre-ICU depression (by proxy method), 15% were above the threshold.


Figure 2
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FIGURE 2.  Distribution of CES–D Score by SCID Diagnostic Categories

MDE: major depressive episode; DD NOS: depressive disorder, not otherwise specified. Data are presented in boxplot format, mean and standard deviation. One outlier case with a CES–D value of 60 in the MDE group is not marked.



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TABLE 2. Test Characteristics of CES–D at Two Cut-Points Versus Two SCID Depression Diagnoses



Predictors of 2-Month and 6-Month Depression Outcome
Regression coefficients in Table 3 showed that worse pre-ICU physical functioning and proxy-endorsed pre-ICU depression were independently associated with a higher depression symptom score at 2 months. In a repeated-measures regression model (Table 4), pre-ICU depression and physical functioning predicted post-ICU depression, independent of follow-up time, although physical functioning was only weakly associated with the CES–D score.


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TABLE 3. Baseline Factors Predicting Square-Root of CES–D at 2 Months




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TABLE 4. Repeated-Measures Analysis Predicting Square-Root of CES–D at 2 and 6 Months



Including all subjects, there was a decrease in the median CES–D scores from 2 to 6 months, although the mean value was stable, and there was a small increase in the proportion of subjects scoring above the threshold (Table 5). This suggests that the skewness of the distribution of depression severity increases from 2 to 6 months as the proportion of subjects with more severe depression increases but the group with less depressive symptoms improves. The presence of 2-month depression was strongly associated (unadjusted relative risk of 4.2 and 4.7) with depression at 6 months. There was no relationship between the change in physical functioning (i.e., 2-month minus baseline) and 2-month CES–D score. This suggests that post-ICU depression severity is unrelated to the extent of patients’ physical decline from baseline. However, the main factor associated with improvement in depressive symptoms from 2 to 6 months was improvement in physical functioning (Spearman {rho} = –0.45; p<0.001), although change in physical functioning explained only 20% of the variance in change in CES–D score over the same interval.


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TABLE 5. CES–D at 2 and 6 Months and Relative Risk of Depression at 6 Months If Depressed at 2 Months



Antidepressant Medications Prescribed After Respiratory Failure
Of all subjects alive at 2 months (N=164), 81 (49%) had taken one or more antidepressant medications between enrollment and first follow-up; 91% of the antidepressants were in the selective serotonin reuptake inhibitor (SSRI) class, and 86% of patients prescribed an SSRI after study entry (prevalent or incident case) were receiving it at 2 months. For subjects surviving to first follow-up who were not taking an antidepressant before ICU treatment (N=109), 31 (28%) were prescribed an antidepressant, and 77% of those were still taking it daily at 2 months. Two subjects started a new antidepressant after the first follow-up. Citalopram (N=13) was the most commonly prescribed new antidepressant, followed by sertraline (N=7) and paroxetine (N=7).

For the group of subjects surviving to first follow-up, Figure 3 shows that patients receiving a new antidepressant were predominantly those requiring inpatient care at 2 months. There is a steeply rising probability of receiving an antidepressant for the group residing in a healthcare facility at 2 months, as compared with the brief rise and plateau for those at home at 2 months (log-rank: 23.6; df=1; p<0.001). We were unable to identify any baseline variables associated with time (latency) to antidepressant prescription.


Figure 3
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FIGURE 3.  Probability of Receiving a New Antidepressant Prescription on the Basis of Subject’s Location at 2-Month Follow-Up

Only cases surviving to first follow-up and without pre-ICU antidepressant use in previous 6 months were analyzed (N=109). Upper curve (solid) represents subjects residing in healthcare facility at first follow-up (N=46), and lower curve (dotted) represents subjects residing at home at first follow-up (N=63). Vertical tick marks represent censored observations completing first follow-up.


In all, 87% of patients with a major depressive episode were prescribed an antidepressant at some time after study enrollment; 64% with depressive disorder not otherwise specified received an antidepressant; and 28% with no current SCID diagnosis at 2 months received at least one dose of an antidepressant.

The 3-month case-fatality rate was 33%. There was no difference in the rate by whether patients were depressed or not in the month before ICU treatment, as determined by proxies (35.5% versus 32.8%; {chi}2=0.18; p=0.67). However, the case-fatality rate was significantly lower in those taking antidepressants in the week before ICU treatment, as compared with subjects not taking antidepressants (23% versus 38%; {chi}2=5.2; p=0.02). This is despite the observation that those taking antidepressants had lower pre-ICU functional status (t-test: SF–36 Physical Functioning domain scores of 27.6 versus 36.8; p=0.04).


  DISCUSSION

 
TOP
 ABSTRACT
 INTRODUCTION
 METHOD
 RESULTS
 DISCUSSION
REFERENCES
 
This study demonstrates the feasibility of characterizing short- and medium-term mood diagnoses from patients recovering from serious medical illnesses and is the first observational study to focus on post-ICU depression and antidepressant therapy. Previous ICU outcome studies have emphasized mortality,17 global quality of life,18,19 posttraumatic stress disorder,20 or cognitive deficits.10,21

We found that one-third of patients surviving to 2-month follow-up have a mood disorder, of which half were major and half subthreshold. Eliminating preexisting cases of depression by two methods yields a point incidence of 25%–28%, with slightly less than one-half of patients defined as major. Although subthreshold depressive symptoms in ambulatory patients are associated with functional impairment and increased service utilization, albeit less than major depression,22,23 the extent to which this is true in severe medical illness requires further study. The depression rate in this study is comparable to previous ICU studies,5–10 although most of the other studies did not perform diagnostic interviews.

Because the acute medical illness precluded a baseline subject interview, it was encouraging that two different methods (proxy-defined and physician prescription-defined) yielded similar incidence results. Proxy–subject agreement about depressive symptoms is less reliable than observable behaviors such as physical functioning,24 and estimates of incidence may be biased if there is ascertainment bias for the baseline status of the subject. Proxies may be more likely to report subjects as non-depressed if they have only mild symptoms, and, therefore, a case of depressive disorder not otherwise specified at 2 months may represent little change from baseline, thereby overestimating the true incidence. Similarly, patients not taking antidepressants may be depressed, whereas those on antidepressants may not have current depressive symptoms. This means that a depression-prevention trial in ICU patients (where a baseline cannot be measured) cannot estimate efficacy by using change scores, as do most depression-treatment studies.

The prevalence and incidence of depressive disorders in these study data are comparable to other studies of acute medical illness, such as stroke, myocardial infarction, and traumatic brain injury,25–27 although selection criteria, diagnostic ascertainment, and follow-up interval vary. Although one-third of patients had a SCID-defined depressive disorder, the severity was mild-to-moderate. The mean CES–D score for patients with MDE or DD NOS was 20.4, and no subject required psychiatric hospitalization, although suicidal ideation was endorsed by 23% of patients with depression.

We identified two baseline factors associated with higher CES–D scores at 2 and 6 months: pre-ICU physical functioning and pre-ICU depression (antidepressant use or proxy-endorsed depression symptoms). Patients with depression had longer hospitalizations and greater physical disability and were more likely to be treated with an antidepressant than were nondepressed subjects. It is possible that subjects with longer hospitalizations had mood symptoms similar to subjects who returned home, but hospitalized subjects were more likely to have their mood symptoms addressed.

An 87% treatment rate for MDE is substantially greater than that for a recent study of hospitalized cancer patients, in which physicians identified only 33% of depressed patients.28 On the other hand, we cannot identify the symptoms or conditions that clinicians were treating in the more than one-quarter of patients who received an antidepressant but had no study-defined disorder during the 2-month interval.

An unexpected and novel finding was that more than one-quarter of subjects were already taking an antidepressant, which raises the clinical quandary of treating critically ill patients receiving chronic psychoactive medications. We are not aware of studies describing the safety of SSRI therapy for ICU patients, but recent reports on bleeding and platelet function suggest caution.29,30 The association between pre-ICU antidepressant use and decreased 3-month mortality must be interpreted cautiously because the antidepressants were non-randomly assigned. It is possible that deteriorating health in the days before respiratory failure prevented some patients from taking their prescribed antidepressant, and it was the rapid decline in health that predicted death, rather than the absence of an antidepressant. Also, many patients on antidepressants who develop acute, severe illnesses have their medications stopped for variable periods of time.

Of all survivors, 49% received antidepressant medications. This is similar to the prevalence (47%) that was previously reported in patients recovering from catastrophic illness at an acute rehabilitation center.31 These data illustrate the widespread use of antidepressants in patients with serious medical illnesses and suggest that additional research on the safety and efficacy of these medications in critically ill patients is needed.

Our data show that the CES–D has excellent discrimination for classifying medically ill subjects as having a major depressive episode or not. At two cut-points, the CES–D is more accurate at ruling out MDE (high negative predictive value), but it also has acceptable positive predictive value if both major and subthreshold depression are included. Although the subjects in this study had substantial medical illness, the sensitivity and specificity for MDE was remarkably similar to the CES–D in outpatient settings: A meta-analysis showed a sensitivity of 0.84 and a specificity of 0.74 for major depressive disorder.32

Subjects with depression at 2 months are at substantial relative risk for persistent depressive symptoms at 6 months. Because changes in physical functioning explained only 20% of the variance in the 2- to 6-month depression change score, we hypothesize that improvement in depression symptoms over time is not solely due to improvement in the general medical condition of the patient.

Limitations of this study include the fact that recruitment at a single, University-based, tertiary-care hospital may decrease generalizability to patients at community hospitals. However, we did enroll a high proportion of eligible medical and surgical patients, and our inclusion criterion of acute respiratory failure was broad. Although we used the SCID interview to classify diagnoses, there is ambiguity about symptom-counting and attributing MDEs to a major depressive disorder or general-medical condition, or adjustment disorder versus depressive disorder, not otherwise specified.33 Because of these nosological difficulties, we a priori planned our analyses using an inclusive counting method34 and the presence of MDE or the A1 or A2 criteria as the two main depression categories. Similarly, our total incidence rate includes both major depressive episodes and depressive disorder not otherwise specified, which is presumably a less-severe condition. It is unclear whether the five-symptom cut-off requirement for a SCID-defined MDE identifies a qualitatively different syndrome from that experienced by those with a lower symptom count but who still complain of depressed mood or anhedonia for more than 2 weeks. There are several studies that suggest a continuum;35–37 others conclude that symptom severity affects prognosis more than does symptom count.38 None of the study subjects had very severe depression; nevertheless, considering the large numbers of patients who survive prolonged mechanical ventilation, the population impact of frequent, but non-severe, depression may still be substantial.

It is sometimes difficult to define explicitly the condition or conditions for which psychiatric medications are prescribed. Although it is possible that some of the incident SSRI medications were prescribed for non-depressive illnesses, such as chronic pain, our review of medical records and subject interviews did not reveal any cases in which SSRIs were prescribed for reasons other than depressive symptoms. For subjects prescribed a new antidepressant, we recorded the dose they were receiving only at the 2- and 6-month follow-up; therefore we cannot determine the frequency of dose-escalation after the initial prescription.

Although we had very good follow-up at 2 months (88%), there was substantial attrition by 6 months, as well as inability to collect data by telephone in very ill patients. Therefore, the longitudinal analyses may be biased, although it is not known whether the direction of bias is to more or less depression.

The observational design precludes drawing inferences about the effectiveness (or safety) of antidepressant therapy for either the group that developed respiratory failure while on chronic antidepressant therapy or those who were prescribed antidepressants during or after respiratory failure. Nevertheless, the hypothesis that depression can be prevented in medical patients is supported by recent trials in immunotherapy and stroke.39,40 We have shown that clinicians prescribe antidepressants to half of all patients who required mechanical ventilation for more than 36 hours. Considering that millions of patients receive ICU care every year, it is important to define the benefits and adverse effects of drug therapy in patients with this condition.


  ACKNOWLEDGMENTS

 
This work was presented in part at the American Thoracic Society International Conference, Seattle, WA, May 19, 2003.

The authors acknowledge the research assistance of Cheryl Stibbe, M.S.N., and Carol Albright, M.S.

The work was supported by NIH grant K23HL04073.


  REFERENCES

 
TOP
 ABSTRACT
 INTRODUCTION
 METHOD
 RESULTS
 DISCUSSION
 REFERENCES
 

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